Alzheimer's disease (AD) is a progressive degenerative disorder of the brain that afflicts over four million people in the United States. No effective treatment is available. The most characteristic change observed upon post-mortem histopathological analysis of AD-afflicted brain tissue is the presence of neuritic and cerebrovascular plaques containing dense deposits of .beta.-amyloid protein (Selkoe, Cell 58:611-612, 1989). .beta.-amyloid is a 39-43 amino acid peptide (Glenner and Wong, biochem. biophys. Res. Commun. 120:885-890, 1984; Masters et al., Proc. Natl. Acad. Aci. USA 82:4345-4249, 1985) synthesized as part of a larger precursor protein referred to as amyloid precursor protein (APP), which is known to have a number of isoforms in humans (APP.sub.695, Kang et al., Nature 325:733-736, 1987; APP.sub.751, Ponte et al., Nature 331:525-527, 1988, and Tanzi et al., Nature 331:528-530, 1988; and APP.sub.770, Kitaguchi et al., Nature 331:530-532, 1988). The amino terminal of .beta.-amyloid is generated by cleavage of a peptide bond of APP which in APP.sub.695 lies between Met596 and Asp597.
Although structural alterations of APP are implicated in the pathogenesis of Alzheimer's disease, it remains unknown how they cause the disease. No biological function for APP has been identified, although there is evidence that APP has a receptor-like architecture (Kang et al., Nature 325:733-736, 1987; Ponte et al., Nature 331:525-527, 1988; Tanzi et al., Nature 331:528-530, 1988; Kitaguchi et al., Nature 331:530-532, 1988), is located on the neuronal surface (Dyrks et al., EMBO J. 7:949-957, 1988), and possesses an evolutionarily conserved cytoplasmic domain (Yamada et al., Biochem. Biophys. Res. Commun. 149:665-671, 1987).